Protein Intake and Mortality in Older Adults With Chronic Kidney Disease

Key Points Question What are the associations of total, animal, and plant protein intake with all-cause mortality in older adults with mild or moderate chronic kidney disease (CKD)? Findings In this cohort study of 8543 community-dwelling adults 60 years and older, higher intake of total, animal, and plant protein was associated with lower mortality in participants with mild or moderate CKD. Associations were larger among participants without CKD. Meaning These findings suggest that the benefits of proteins may outweigh the downsides in older adults with mild or moderate CKD, in whom disease progression may play a more limited role in survival.


Introduction
Aging is characterized by multiple behavioral and physiological changes across organs and systems that impair protein utilization and increase its requirements. 1,2On the one hand, protein synthesis is reduced because of a shortage of available nutrients due to loss of appetite, sedentary behavior, and insulin and protein anabolic resistance. 1,2On the other hand, protein degradation, increased oxidative modification of proteins, and accumulation of inflammatory diseases lead to an increased need for protein. 1,22][3] Additional increases may be warranted for those with acute and multiple chronic diseases and those with severe illness, injuries, or malnutrition. 1,2ile older adults may need more protein than younger persons, higher protein intake could accelerate disease progression among those with chronic kidney disease (CKD), a prevalent condition in older adults that often has no cure and high morbidity and mortality. 4,5According to current guidelines, adults with mild CKD (stages 1 and 2) are advised to avoid high protein intake (>1.305][6] The latest guidelines leave the door open for higher protein intake targets in those with underlying conditions, such as frailty and sarcopenia, but more data are needed to make specific recommendations. 5Observational studies on mortality in older persons with CKD are often small to moderate in size, are conducted in a single setting, and use point-in-time estimates of protein intake, [10][11][12] while randomized clinical trials commonly include participants with CKD of all ages and lack power to analyze protein intake modification in those who are older. 13,14e role of protein sources in older adults with CKD is also of interest.5,16 Nevertheless, whether a diet that is high in plant protein could provide the benefits of higher protein intake without the known downsides in older adults with CKD remains to be investigated.
In this study, we pooled longitudinal data from 3 cohorts to estimate the associations of total, animal, and plant protein intake with all-cause mortality in older persons with mild or moderate CKD and compared the results with those of older adults without CKD.To examine age-related physiological changes and allow for better risk stratification, we also analyzed the differences between participants younger than 75 years vs 75 years or older.

JAMA Network Open | Nutrition, Obesity, and Exercise
Protein Intake and Mortality in Older Adults With CKD

Study Design and Participants
This multicohort study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational cohort studies.Three studies were included in the analyses.The Study on Cardiovascular Health, Nutrition and Frailty in Older Adults in Spain (Seniors-ENRICA) 1 and 2 are cohorts of randomly sampled, community-dwelling individuals in Spain 60 years and older and 65 years and older, respectively. 17,18To maximize the use of dietary

Study Variables Diet
Habitual food consumption in the previous year was obtained with an interviewer-administered, validated electronic dietary history in 3 of the 4 waves of Seniors-ENRICA 1 and in 2 of the 3 waves of Seniors-ENRICA 2. 21 To convert food consumption into nutrients, the dietary history used data from Spanish and other standard food composition tables. 21In all SNAC-K waves, dietary data were collected with a self-administered, semiquantitative, validated food frequency questionnaire that consisted of 98 foods and beverages. 22Household measures and food composition tables from the Swedish National Food Agency were used to estimate nutrient intake. 22oteins were deemed to have plant or animal origin according to the foods from which they came.Cereal, legume, nut, and other vegetable proteins were considered plant proteins, while dairy, meat, egg, fish, and other animal proteins were considered of animal origin.

Chronic Kidney Disease
In all cohorts, the estimated glomerular filtration rate (eGFR) was calculated using the Berlin Initiative Study equation, which is specifically tailored for older adults: 3736 × Serum Creatinine Level −0.87 × Age −0.95 × 0.82 (if female). 23For participants from the Seniors-ENRICA cohorts who provided spot urine samples, albumin level of at least 20 mg/L (to convert to g/L, divide by 1000) was used as a measure of kidney damage, as it has shown high specificity for urinary albumin excretion of at least 30 mg in 24 hours. 24In addition, we used inpatient and outpatient medical records in SNAC-K, as well as primary care records in Seniors-ENRICA 2. We also used information on deaths with CKD between data collection waves in Seniors-ENRICA 1 and SNAC-K, and we identified those participants undergoing kidney replacement therapy and kidney transplant via International Statistical Classification of Diseases, Tenth Revision, codes.We defined CKD as an eGFR of less than 60 mL/min/1.73m 2 , high urine albumin level, an antemortem or postmortem medical diagnosis, kidney replacement therapy, or kidney transplant.Participants with CKD were grouped into stages 1 to 5 from the Kidney Disease: Improving Global Outcomes guidelines. 5

Mortality
In the Seniors-ENRICA cohorts, mortality was ascertained with the Spanish National Death Index.In the SNAC-K cohort, such information was available from the Swedish Cause of Death Register.Data were available until December 2021 in SNAC-K and until January 2024 in Seniors-ENRICA 1 and 2. 17,23 Other Variables Potential confounders included sex, age, living arrangement, previous occupation, educational level, tobacco smoking, light and moderate-to-vigorous physical activity, body mass index, diabetes, cardiovascular disease, chronic lung disease, musculoskeletal disease, cancer, depression and mood disorders, and intake of energy, monounsaturated fat, sugar, alcohol, and sodium.Race and ethnicity were not considered due to data not being available in Seniors-ENRICA 2 and SNAC-K.Information on potential confounders and their data sources can be found in eMethods 1 in Supplement 1.

Analytical Sample
Of 10 149 recruited participants, we excluded 1566 who had no information on diet and 1 who had no information on mortality.We additionally excluded participants with CKD stages 4 or 5 (n = 30), those undergoing kidney replacement therapy (n = 7), and kidney transplant recipients (n = 2). 4,6nce, the analytical sample comprised 8543 persons and 14 399 observations (4789 with CKD and 9610 without).The same criteria were used to exclude participant observations during the follow-up (eFigure 1 in Supplement 1).

Statistical Analysis Main Analyses
Data were originally analyzed from June 2023 to February 2024 and reanalyzed in May 2024.
Associations of protein intake with mortality were summarized with hazard ratios (HRs) and 95% CIs and estimated with Cox proportional hazards regression.To represent longer-term dietary intake and minimize within-person variation, we implemented the Andersen and Gill 25 model and set up the data so that there was 1 observation per time interval for each participant.For each observation, we used the cumulative mean of protein intake and continuous potential confounders and the most recent information on CKD and categorical potential confounders. 26All models were adjusted for cohort and the previously mentioned sociodemographic, lifestyle, morbidity, and dietary variables.
To increase comparability of results across cohorts, participants were censored at 10 years of follow-up.
Protein intake was expressed as grams per kilogram of body weight per day. 1,2,5,6To better capture nonlinear trends and minimize power loss, total protein intake was rounded to the nearest 0.05 and modeled as a restricted cubic spline. 27Hazard ratios were evaluated at equally spaced intervals between 0.8 and 1.6 g/kg/d of total protein intake in the Tables and at all the distinct observed values in the Figures.We considered 0.8 g/kg/d the protein intake reference value in both Tables and Figures. 1,2,5,6We also modeled total protein intake as a linear variable (per 0.2-g/kg/d increment).Animal and plant protein intake were operationalized using similar procedures, as were the main animal and plant protein sources (ie, dairy, meat, fish, and cereal).
To account for incomplete information in the datasets, we used multiple imputation by chained equations (eMethods 2 in Supplement 1).The number of participant observations with missing data for each variable, collection wave, and cohort can be found in eTable 1 in Supplement 1.

Interactions and Ancillary Analyses
Hazard ratios and 95% CIs were obtained from models with 2-way multiplicative interactions between total protein intake and CKD and 3-way multiplicative interactions among protein intake, CKD, and age (<75 vs Ն75 years).Differences in the strength of study associations across subgroups were evaluated with P values for interaction, obtained from Wald tests of linear hypotheses.
Additional interactions among total protein intake, CKD, and cohort and among the former 2 variables and sex were explored in ancillary analyses.Beyond total protein intake, we built models integrating multiplicative interactions between animal protein intake and CKD and between plant protein intake and CKD (and age, as appropriate).All models included both main effects and interaction terms, significance level was set at α<.05, and hypothesis tests were 2 sided.We also assessed how changes in protein intake (from baseline to the nearest available follow-up) and the proportion of plant protein were associated with mortality.To test the robustness of our results, we conducted 15 sensitivity analyses, which are described in detail in eMethods 3 in Supplement 1.All statistical analyses were performed using Stata, version 18.0 (StataCorp LLC).

Descriptive and Outcome Data
Characteristics of 14 399 participant observations stratified by CKD are shown in

Discussion Interpretation
Results of this multicohort study are in line with those of observational studies [10][11][12] that have found neutral or inverse associations between protein intake and mortality among older persons with CKD stages 3 to 5 not receiving dialysis.First, in 3892 middle aged and older Korean adults, higher total protein intake showed a null association with 11-year all-cause mortality. 10Second, among 356 French patients with CKD over 60 years, higher total protein intake was not associated with increased mortality after 3 years. 12Third, in 259 Japanese adults with CKD and older than 65 years, higher total protein intake was associated with lower risk of all-cause death over 4 years, although participants had been advised to limit protein intake depending on their CKD stage. 11e latest Cochrane systematic reviews 13,14 of randomized clinical trials found that among adults of all ages without diabetes and with CKD, protein intake of either 0.30 to 0.40 or 0.50 to 0.60 g/kg/d probably does not influence the risk of death when compared with 0.80 g/kg/d or Abbreviations: CKD, chronic kidney disease; HR, hazard ratio.
a Calculated with Cox proportional hazards regression models.Protein intake was modeled as a continuous variable (per 0.20 g/kg/d) or a 3-knot restricted cubic spline otherwise.Hazard ratios (95% CIs) were obtained from models with multiplicative interaction terms between protein intake and CKD.Models on protein sources integrated multiplicative interactions between animal protein intake and CKD and between plant protein intake and CKD.Models were adjusted for cohort, sex, age, living arrangement, previous occupation, educational level, tobacco smoking, light physical activity, moderate-tovigorous physical activity, body mass index, diabetes, cardiovascular disease, chronic lung disease, musculoskeletal disease, cancer, depression and mood disorders, and intake of energy, monounsaturated fat, sugar, alcohol, and sodium.
greater, while in adults with diabetic kidney disease, protein intake of 0.60 to 0.80 g/kg/d may make little difference in the risk of mortality when compared with 1.00 g/kg/d or greater.
In our analyses, we observed an inverse association between total protein intake and mortality among participants with CKD but a somewhat weaker one than among those without CKD.Together  Analyses used Cox proportional hazards regression models.Protein intake was modeled as a 3-knot restricted cubic spline.Hazard ratios (HRs) and 95% CIs were plotted for protein intake above the 1st percentile and below the 99th percentile and obtained from models with interaction terms among protein intake, chronic kidney disease, and age.Models were adjusted for cohort, sex, age, living arrangement, previous occupation, educational level, tobacco smoking, light physical activity, moderate-to-vigorous physical activity, body mass index, diabetes, cardiovascular disease, chronic lung disease, musculoskeletal disease, cancer, depression and mood disorders, and intake of energy, monounsaturated fat, sugar, alcohol, and sodium.
with the previous studies, this suggests that the benefits of proteins may outweigh the risks in older adults with mild or moderate CKD, in whom disease progression may play a more limited role in survival.
Specifically, protein deficiency in older adults may cause impairments of muscular, skeletal, and immune function, while higher protein intake has been associated with increased muscle mass and strength, slower rate of bone loss, higher bone mineral density, lower risk of frailty, and improved cardiovascular function and recovery from illness (including wound healing). 1,2Protein supplementation appears to reduce the risk of death in older persons (possibly by elevating branched-chained amino acid levels), especially in older patients and in the presence of malnutrition or other geriatric syndromes. 1,2,28,29idence linking protein intake to CKD progression in older adults exists as well, although it is not as consistent.In 3 cohort studies totaling more than 2700 participants, 11,30,31 one report found slower eGFR decline and another found faster eGFR decline but similar risk of end-stage kidney disease linked to higher protein intake.In the same cohorts, analyses of protein sources showed that plant protein was either not associated with eGFR changes or associated with a slower decline in kidney function. 30,31Randomized clinical trials indicate that, among adults with diabetic Analyses used Cox proportional hazards regression models.Protein intake was modeled as a 3-knot restricted cubic spline.Hazard ratios (HRs) and 95% CIs were plotted for protein intake above the 1st percentile and below the 99th percentile and obtained from models integrating interaction terms among animal protein intake, chronic kidney disease, and age and among plant protein intake, chronic kidney disease, and age.
variables and others, we took data from 4 waves of Seniors-ENRICA 1 (March 2008 to September 2010, February to November 2012, November 2014 to June 2015, and January to July 2017) and 3 waves of Seniors-ENRICA 2 (December 2015 to June 2017, September 2018 to October 2019, and November 2021 to February 2023).The Clinical Research Ethics Committee of the La Paz University Hospital in Madrid approved the research protocols, and all participants gave written informed consent at each study visit.The Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) is a longitudinal, community-based cohort of randomly sampled adults 60 years or older living in Stockholm, Sweden. 19,20All participants attended examinations in March 2001 to August 2004 and February 2007 to October 2010, and those 78 years and older were also assessed in November 2004 to May 2007.SNAC-K was approved by the Regional Ethical Review Board in Stockholm, and written informed consent was obtained from participants or their next of kin.

Figure 1 .
Figure 1.Association of Total Protein Intake With 10-Year All-Cause Mortality, Stratified by Chronic Kidney Disease and Age

Figure 2 .
Figure 2. Associations of Animal and Plant Protein Intake With 10-Year All-Cause Mortality, Stratified by Chronic Kidney Disease and Age

Table 1 .
Characteristics of the Participant Observations, Stratified by CKD

Table 2 .
Associations of Total, Animal, and Plant Protein Intake With 10-Year All-Cause Mortality, Stratified by CKD

Table 3 .
Associations of Total, Animal, and Plant Protein Intake With 10-Year All-Cause Mortality, Stratified by CKD and Age Models were adjusted for cohort, sex, age, living arrangement, previous occupation, educational level, tobacco smoking, light physical activity, moderate-to-vigorous physical activity, body mass index, diabetes, cardiovascular disease, chronic lung disease, musculoskeletal disease, cancer, depression and mood disorders, and intake of energy, monounsaturated fat, sugar, alcohol, and sodium.Participant Observations With Missing Data for Each Variable, Time Point, and Cohort eTable 2. Characteristics of the Participant Observations, Stratified by Chronic Kidney Disease and Age eTable 3. Characteristics of the Participant Observations, Stratified by Chronic Kidney Disease and Cohort eTable 4. Hazard Ratios (95% CIs) of the Associations of the Main Sources of Animal and Plant Protein Intake With 10-Year All-Cause Mortality, Stratified by Chronic Kidney Disease eTable 5. Hazard Ratios (95% CIs) of the Associations of Changes in Total, Animal, and Plant Protein Intake With 10-Year All-Cause Mortality, Stratified by Chronic Kidney Disease eTable 6. Sensitivity Analyses: Hazard Ratios (95% CIs) of the Associations of Total, Animal, and Plant Protein Intake With 10-Year All-Cause Mortality, Stratified by Chronic Kidney Disease JAMA Network Open | Nutrition, Obesity, and Exercise Protein Intake and Mortality in Older Adults With CKD Participants' Flowchart, Stratified by Cohort eFigure 2. Association of Total Protein Intake With 10-Year All-Cause Mortality, Stratified by Chronic Kidney Disease and Cohort eFigure 3. Association of Total Protein Intake With 10-Year All-Cause Mortality, Stratified by Chronic Kidney Disease and Sex eFigure 4. Association of the Proportion of Plant Protein With 10-Year All-Cause Mortality, Stratified by Chronic Kidney Disease and Age eReferences.